The cyclin-dependent kinases, or "CDKs", are a family of proteins involved in cell-cycle regulation. The CDKs are only active as kinases when they associate with other proteins known as cyclins, on which they are dependent. The manner by which the CDKs control cell cycle regulation has, however, only recently begun to be explained.
Y. Xiong et al., Cell 71, 505-514 (1992) showed that, in vivo in normal human fibroblasts, there exists a quaternary complex of cyclin D, p21, CDK, and proliferating cell nuclear antigen (or "PCNA"). See also H. Zhang et al., Molec. Biol. Cell 4, 897 (1993); Y. Xiong et al., Genes & Development 7, 1572 (1993). These results indicated that in addition to the cyclin activation and subunit phosphorylation, the activity of CDKs may be controlled by a number of small proteins (e.g., p21.sup.WAF1/Cip1/Sdi1 and p16.sup.INK4) that physically interact with cyclins, CDKs or cyclin-CDK complexes.
Y. Xiong et al., Nature 366, 701-704 (16 Dec. 1993), describes the cloning of p21 and shows that p21 is an inhibitor of cyclin kinases (p21 had previously been cloned and described as a senescent cell-derived inhibitor, or "sdi", by J. R. Smith, U.S. Pat. No. 5,302,706). This work and the work of others (see El-Deiry et al., Cell 75, 817-825 (1993) further shows that p21 is upregulated by the upregulation of the tumor supressor protein p53. By showing that p21 is under the control of p53, this work indicates that the p21 serves as a critical link between the tumor supressor protein p53 and the CDK cell cycle control mechanisms.
A. Kamb et al., Science 264, 436-440 (15 Apr. 1994) and T. Noborl et al., Nature 368, 753-756 (21 Apr. 1994) describe the isolation of the multiple tumor supressor 1 and 2 DNA, (or "MTS1" and "MTS2"), which encode the CDK4 inhibitor p16 (previously identified in M. Serrano et al., Nature 366, 704-707 (16 Dec. 1993)). It is suggested that both p16 and p21 are expected to antagonize entry into the S phase of the cell cycle, and that in vitro p16 appears more specific than p21.